Cardiovascular disease (CVD) generally includes coronary artery disease, cerebrovascular disease and peripheral arterial disease, and is the major cause of morbidity and mortality in the Western world. (Brunzell et al. Lipoprotein Management in Patients with Cardiometabolic Risk, Diabetes Care 2008 31: 811-822). Notwithstanding significant improvements in therapeutic options over the last few decades, the initial presentation of coronary arterial disease in particular manifests as sudden death in up to one-third of patients. Id. Accordingly, better and more effective intervention options are still needed to prevent atherosclerosis and/or reduce its rate of progression once the disease process is initiated.
To more effectively address this rapidly growing public health problem the American Diabetes Association and the American College of Cardiology Foundation have jointly developed and advocated for the treatment of cardiometabolic risk (CMR), which refers to a high lifetime risk of CVD. (Eckel et al. Preventing Cardiovascular Disease and Diabetes, Diabetes Care 2006 29:1697-1699). Notably, the risk factors for cardiovascular disease and type 2 diabetes often cluster, including obesity, insulin resistance, hyperglycemia, dyslipoproteinemia and hypertension. When patients have one or more of these risk factors and are physically inactive or smoke, their cardiometabolic risk increases even further.
Lipoprotein abnormalities, including elevated triglycerides, low HDL cholesterol, and increased LDL are common findings in patients with CMR. As such, administration of therapeutic agents directed at lowering LDL cholesterol such as, e.g., statins can reduce the risk of CVD events in diabetic patients, and in non-diabetic patients having other CVD risk factors. Even with adequate cholesterol lowering, however, many patients on statin therapy still have significant CVD risk. (See Brunell, supra). Accordingly, more effective therapies are clearly still needed to better address this multivariate and complex series of disorders.
The impact of certain hypoglycemic agents such as pioglitazone and glimepiride on atherosclerotic plaque formation in diabetic patients has been evaluated. The PERISCOPE study compared pioglitazone with glimepiride in diabetics; atherosclerotic plaque volume was measured and followed over time. Nissen et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes”. JAMA 2008 299 (13): 1561-73. Glimepiride therapy had highly significant progression of plaque volume over time of 0.73 percent. In comparison, pioglitazone had a −0.16 percent regression in plaque volume. Notably, however, to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications. Id.
Metformin is commonly prescribed for glycemic control in patients having type II diabetes, and has also been shown to improve serum lipids, decreasing triglycerides, free fatty acids, and LDL-cholesterol and modestly increasing HDL-cholesterol. (Bailey & Turner Metformin. N Engl J Med. 1996 Feb. 29; 334(9) Unfortunately, however, metformin also produces significant gastrointestinal complications that have restricted its use beyond diabetic patients per se, and it is further contraindicated in patients having hypoxic conditions caused by, e.g. respiratory or heart failure. Moreover, conventional dosing strategies require a gradual dose escalation from 500 mg bid up to 1000 mg bid for a daily maximum dose of 2000 mg, with further uptitration to as much as 3000 mg/day to achieve appropriate glycemic control, severely limiting the ability of formulators to combine it with additional active agents in fixed dose combination therapies. To date, it has proven difficult to effectively combine metformin with multiple active agents in the same single-dose formulation.
Clearly then, there continues to be a need for more comprehensive approach to reducing cardiometabolic risk in general, and for treating and/or preventing cardiovascular disease in particular.